Trial Outcomes & Findings for A Multicenter Study to Evaluate the Efficacy and Safety of Cinryze® for the Treatment of Acute Antibody-mediated Rejection in Participants With Kidney Transplant (NCT NCT02547220)

Last Updated: 2020-07-13

Results Overview

New or worsening TG at month 6 by the standard score was defined as an increase in one or more between qualifying biopsy and 6-month biopsy. New or worsening TG was measured by Banff 2013 criteria (standard score) using allograft glomerulopathy (Cg0-Cg3): Cg0- No GBM double contours by light microscopy (LM) or electron microscopy (EM); Cg1- no GBM double contours by LM but GBM double contours in at least 3 glomerular capillaries by EM; Cg2- Double contours affecting 26 to 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli; Cg3- Double contours affecting more than 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli with a score range of 0 (no allograft glomerulopathy) and 3 (severe glomerulopathy). Percentage of participants with new or worsening TG at Month 6 post-treatment was reported.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

39 participants

Primary outcome timeframe

Month 6

Results posted on

2020-07-13

Participant Flow

The study was conducted at 49 sites between 20 May 2016 (first participant first visit) and 31 May 2019 (last participant last visit).

A total of 39 participants were randomized and received treatment.

Participant milestones

Participant milestones
Measure	Placebo Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9 percent \[%\] sodium chloride) on day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.	CINRYZE Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.
Overall Study STARTED	19	20
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	19	20

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9 percent \[%\] sodium chloride) on day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.	CINRYZE Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.
Overall Study Withdrawal by Subject	1	0
Overall Study Study terminated by sponsor	18	20

Baseline Characteristics

A Multicenter Study to Evaluate the Efficacy and Safety of Cinryze® for the Treatment of Acute Antibody-mediated Rejection in Participants With Kidney Transplant

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=19 Participants Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9% sodium chloride) on day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.	CINRYZE n=20 Participants Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.	Total n=39 Participants Total of all reporting groups
Age, Continuous	51.9 Years STANDARD_DEVIATION 12.49 • n=5 Participants	49.2 Years STANDARD_DEVIATION 13.45 • n=7 Participants	50.5 Years STANDARD_DEVIATION 12.90 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	5 Participants n=7 Participants	14 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	15 Participants n=7 Participants	25 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants n=5 Participants	10 Participants n=7 Participants	23 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized White	12 Participants n=5 Participants	13 Participants n=7 Participants	25 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian/Non-Japanese	5 Participants n=5 Participants	1 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized Asian/Japanese	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Latino	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Unknown	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Month 6

Population: FAS consisted of all participants who had taken at least 1 dose of investigational product.

Outcome measures

Outcome measures
Measure	Placebo n=19 Participants Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9% sodium chloride) on day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.	CINRYZE n=20 Participants Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.
Percentage of Participants With New or Worsening Transplant Glomerulopathy (TG) at Month 6 Post-Treatment	47.4 Percentage of participants	50.0 Percentage of participants

SECONDARY outcome

Timeframe: Month 48

Population: This study was prematurely terminated at Month 36 due to futility issue. This outcome measure was planned to analyze at Month 48. Hence, data for this outcome measure was not collected as planned, analyzed and reported.

Graft failure was determined as the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment more than \[\>\] 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and estimated glomerular filtration rate (eGFR) less than or equal to (\<=) 15 milliliter (mL)/minute (min)/1.73 meter (m)\^2.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, up to Month 48

Renal function was measured as glomerular filtration rate calculated by the modification of diet in renal disease (eGFRMDRD).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Pre-AMR Baseline, up to Month 48

Renal function was measured as glomerular filtration rate calculated by the modification of diet in renal disease (eGFRMDRD). Pre-AMR baseline was the highest eGFRMDRD value obtained following the kidney transplant and within 30 days prior to the qualifying AMR episode.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Month 48

Proteinuria included spot urine protein, urine creatinine, and urine protein/urine creatinine ratio.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Pre-AMR Baseline, Month 6

Population: This study was prematurely terminated at Month 36 due to futility issues. The data of this secondary outcome measure was not collected as planned and the secondary analysis was not performed, due to early study termination.

Histopathological diagnosis of acute rejection was measured by Banff 2013 criteria: Glomerulitis score (g0-g3), allograft glomerulopathy (Cg0-cg3), Tubulitis score (T0-T3), Intimal arteritis score (V0-V3), peritubular capillaritis (PTC) (ptc0-ptc3) and Interstitial Inflammation score (i0-i3). The histopathology was a composite of the sub-scores. Each of the sub-scores or histopathology score ranges from 0 ( no histopathology) to 3 (more severe histopathology).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Month 6

Graft failure was determined by the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment more than \[\>\] 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and estimated glomerular filtration rate (eGFR) less than or equal to (\<=) 15 milliliter (mL)/minute (min)/1.73 meter (m)\^2.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Month 48

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Month 48

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Month 48

Graft failure was determined by the presence of one or more of the following criteria: institution of permanent dialysis (defined as dialysis treatment \> 30 days), current transplant nephrectomy, and/or a clinical determination of cessation of kidney graft function and eGFR \<=15 mL/ min/1.73m\^2. Time to graft failure due to AMR episodes in months was calculated as (Date of graft failure due to AMR - Date of first dose + 1)/30.25.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Month 48

Number of participants with resolution of the qualifying AMR episodes at Month 48.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Month 48

Time to resolution of qualifying AMR episodes was calculated as (Date of qualifying AMR resolution - Date of first dose + 1)/30.25. Participants who didn't had resolution of qualifying AMR episodes and still on-study were censored at the date of last visit; Participants who had completed the study without resolution of qualifying AMR were censored at the date of study completion; participants who discontinued from the study without resolution of qualifying AMR were censored at the date of early discontinuation.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Month 36

Population: Safety analysis set consisted of all participants who had taken at least 1 dose of investigational product. This study was prematurely terminated at Month 36 due to futility issue. This outcome measure was planned to analyze at Month 48.

Number of participants who were alive at Month 36 (study terminated instead of Month 48) were reported.

Outcome measures

Outcome measures
Measure	Placebo n=19 Participants Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9% sodium chloride) on day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.	CINRYZE n=20 Participants Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.
Number of Participants Who Were Alive at Month 36	19 Participants	20 Participants

SECONDARY outcome

Timeframe: Up to Month 48

Time to all-cause mortality was calculated as (Date of discontinuation due to death - Date of first dose + 1)/30.25. Participants who are alive and still on-study were censored at the date of last visit; Participants who had completed the study were censored at the date of study completion; Participants who discontinued from the study but not due to death were censored at the date of early discontinuation.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From start of study drug administration up to study termination (Month 36)

Population: Safety analysis set consisted of all participants who had taken at least 1 dose of investigational product.

An adverse event (AE) was any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurred in a participant participating in a clinical study with the sponsor's product, regardless of causal relationship. TEAEs were defined as events that started or worsened on or after the date of the first dose of investigational product, but no later than 30 days following the last dose of investigational product, within a treatment period.

Outcome measures

Outcome measures
Measure	Placebo n=19 Participants Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9% sodium chloride) on day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.	CINRYZE n=20 Participants Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	16 Participants	16 Participants

Adverse Events

Placebo

Serious events: 6 serious events

Other events: 15 other events

Deaths: 0 deaths

CINRYZE

Serious events: 3 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=19 participants at risk Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9% sodium chloride) on day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.	CINRYZE n=20 participants at risk Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.
Gastrointestinal disorders Gastrointestinal haemorrhage	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
General disorders Catheter site thrombosis	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Immune system disorders Anaphylactic shock	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Infections and infestations Klebsiella sepsis	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Infections and infestations Pneumonia	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Injury, poisoning and procedural complications Arteriovenous fistula thrombosis	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Renal and urinary disorders Renal impairment	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)

Other adverse events

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=19 participants at risk Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of placebo (100 mL 0.9% sodium chloride) on day 1 followed by 2500 units of placebo (100 mL 0.9% sodium chloride) on Days 3, 5, 7, 9, 11, and 13.	CINRYZE n=20 participants at risk Participants received a total of seven doses with an initial 100 mL intravenous (IV) infusion containing 5000 units of CINRYZE on Day 1 followed by 2500 units of CINRYZE in 100 mL of IV infusion on Day 3, 5, 7, 9, 11, and 13.
Blood and lymphatic system disorders Anaemia	10.5% 2/19 • Number of events 2 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Blood and lymphatic system disorders Leukopenia	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	10.0% 2/20 • Number of events 2 • From start of study drug administration up to study termination (Month 36)
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Musculoskeletal and connective tissue disorders Muscle spasms	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Vascular disorders Hypertension	10.5% 2/19 • Number of events 3 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 2 • From start of study drug administration up to study termination (Month 36)
Vascular disorders Lymphocele	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Vascular disorders Orthostatic hypotension	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Gastrointestinal disorders Abdominal pain	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Gastrointestinal disorders Constipation	10.5% 2/19 • Number of events 2 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Gastrointestinal disorders Diarrhoea	10.5% 2/19 • Number of events 2 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Gastrointestinal disorders Dry mouth	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Gastrointestinal disorders Flatulence	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Gastrointestinal disorders Nausea	10.5% 2/19 • Number of events 2 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Gastrointestinal disorders Oesophagitis	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Gastrointestinal disorders Tooth disorder	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Gastrointestinal disorders Vomiting	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
General disorders Asthenia	10.5% 2/19 • Number of events 2 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
General disorders Fatigue	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
General disorders Malaise	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
General disorders Nodule	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
General disorders Non-cardiac chest pain	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
General disorders Oedema peripheral	10.5% 2/19 • Number of events 2 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Cardiac disorders Bradycardia	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Infections and infestations BK virus infection	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Infections and infestations Catheter site infection	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Infections and infestations Clostridium difficile colitis	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Infections and infestations Cytomegalovirus infection	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Infections and infestations Peritonitis	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Infections and infestations Upper respiratory tract infection	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Infections and infestations Urinary tract infection bacterial	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Infections and infestations Urosepsis	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Injury, poisoning and procedural complications Arteriovenous fistula site haematoma	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Injury, poisoning and procedural complications Citrate toxicity	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 5 • From start of study drug administration up to study termination (Month 36)
Injury, poisoning and procedural complications Complications of transplanted kidney	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Injury, poisoning and procedural complications Toxicity to various agents	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Injury, poisoning and procedural complications Vascular access complication	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Investigations Alanine aminotransferase increased	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Investigations Aspartate aminotransferase increased	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Investigations Blood bicarbonate decreased	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Investigations Blood bicarbonate increased	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Investigations Blood creatinine increased	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Investigations Blood glucose increased	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Investigations Blood magnesium decreased	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Investigations Blood phosphorus decreased	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Investigations Blood potassium increased	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Investigations Blood urea increased	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Investigations Blood uric acid increased	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Investigations Glomerular filtration rate decreased	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Investigations Haemoglobin decreased	10.5% 2/19 • Number of events 2 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Investigations Neutrophil count increased	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Investigations White blood cell count increased	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Renal and urinary disorders Acute kidney injury	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Renal and urinary disorders Chronic kidney disease	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Renal and urinary disorders Proteinuria	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Metabolism and nutrition disorders Diabetes mellitus	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	10.0% 2/20 • Number of events 2 • From start of study drug administration up to study termination (Month 36)
Metabolism and nutrition disorders Folate deficiency	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Metabolism and nutrition disorders Hyperglycaemia	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Metabolism and nutrition disorders Hypokalaemia	10.5% 2/19 • Number of events 2 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Metabolism and nutrition disorders Hypomagnesaemia	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Metabolism and nutrition disorders Hypophosphataemia	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Metabolism and nutrition disorders Metabolic acidosis	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Nervous system disorders Dizziness	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Nervous system disorders Headache	5.3% 1/19 • Number of events 3 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Nervous system disorders Hypoaesthesia	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Nervous system disorders Tremor	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Psychiatric disorders Anxiety	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Respiratory, thoracic and mediastinal disorders Dry throat	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Respiratory, thoracic and mediastinal disorders Epistaxis	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Respiratory, thoracic and mediastinal disorders Sinus disorder	5.3% 1/19 • Number of events 1 • From start of study drug administration up to study termination (Month 36)	0.00% 0/20 • From start of study drug administration up to study termination (Month 36)
Respiratory, thoracic and mediastinal disorders Throat irritation	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Skin and subcutaneous tissue disorders Rash pruritic	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/19 • From start of study drug administration up to study termination (Month 36)	5.0% 1/20 • Number of events 1 • From start of study drug administration up to study termination (Month 36)